title: Proinflammatory stimuli induce galectin-9 in human mesenchymal stromal cells to suppress T-cell proliferation.
abstract: Human multipotent mesenchymal stromal cells (MSCs) are clinically applied to treat autoimmune diseases and graft-versus-host disease due to their immunomodulatory properties. Several molecules have been identified to mediate these effects, including constitutively expressed galectin-1. However, there are indications in the literature that MSCs exert enhanced immunosuppressive functions after interaction with an inflammatory environment. Therefore, we analyzed how inflammatory stimuli influence the expression of the galectin network in MSCs and functionally tested the relevance for the immunomodulatory effects of MSCs. We found that galectin-9 was strongly induced in MSCs upon interaction with activated PBMCs. Proinflammatory cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), and also ligands of the Toll-like receptors (TLRs) TLR2, TLR3, and TLR4 elicited similar induction of galectin-9 in activated PBMCs. Galectin-9 was not only upregulated intracellularly, but also released by MSCs in significant amounts into the supernatant after exposure to proinflammatory stimuli. In proliferation assays, MSCs with a galectin-9 knockdown lost a significant portion of their antiproliferative effects on T cells. In conclusion, we found that unlike constitutively expressed galectin-1, galectin-9 is induced by several proinflammatory stimuli and released by MSCs. Thus, galectin-9 contributes to the inducible immunomodulatory functions of MSCs.
authors.affiliation: Research Institute Children's Cancer Center, Hamburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Gieseke
authors.forename: Anne
authors.initials: A
authors.lastname: Kruchen
authors.forename: Nikolay
authors.initials: N
authors.lastname: Tzaribachev
authors.forename: Frank
authors.initials: F
authors.lastname: Bentzien
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.forename: Ingo
authors.initials: I
authors.lastname: Müller
mesh_terms: D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D049109:Cell Proliferation; D002478:Cells, Cultured; D037161:Galectins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D037161:Galectins; C105032:LGALS9 protein, human; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Galectin-9; Immunosuppressive effects; Mesenchymal stromal cells; Proinflammatory stimuli; T-cell proliferation